Variation of Comparative Dissolution Test of Atorvastatin :

A Review on Biopharmaceutics Study

Nama
Faculty of Pharmacy, Universitas Padjadjaran
Jl. Raya Bandung Sumedang KM 21, Jatinangor Indonesia
Email:

Abstract
Comparative Dissolution Test is a test that conducted to show the similarity
or different dissolution profiles between test drugs and innovator/comparator drugs.
Comparative Dissolution Test may also be used to ascertain the equivalence and
product properties of a pharmaceutical product. Atorvastatin is one of the most
common synthetic statins in the world. This drug patent runs out in 2011. This drug
is at the top of the list of drugs with the largest sales for many years until 2011. The
purpose of this review is to find out whether different dissolution profile methods
can be applied in conducting comparative dissolution test studies of atorvastatin
and evaluating each method of different calculation methods to obtain dissolution
profile values. Based on the analysis of these methods, it can be concluded that each
method has different characteristics in looking for dissolution profiles. The labeled
atorvastatin inovator and generic samples of tablets meet all the physical
requirements of the tablet, while generic atorvastatin tablets do not meet any of the
tablet's physical requirement.

Keywords: Biopharmaceutics, Comparative Dissolution Testing, Simvastatin

INTRODUCTION
Drugs with the same ingredients and
active compounds are on the market with
different name of brand. Different products
with the same amount of Active
Pharmaceutical Ingredients (APIs) can result
differences in each therapeutic effects
(Esimone et al., 2008). This aspect can be
happened due to differences in absorption
rate, the difference between the purity of the
active ingredient, the type of excipient, the
manufacturing variables such as the mixing
method and the granulation procedure also
the coating parameter.
A pharmaceutical preparation
should meet three main kriteria including
safety, efficacy, and quality. For innovator
products, the evaluation of these three aspects
should be done comprehensively, begin from
the pre-clinical trials, clinical trials, result in
post-marketing surveillance at enormous
cost. However, for generic drug products
(copy drug), it is required to meet the
requirements of equivalence test both in vitro
and in vivo test (Badan POM RI, 2004).
In vitro bioequivalence test can be
performed using comparative dissolution test
method using three different dissolution
medium including hydrochloric acid (HCl)
medium pH 1.2 or simulated gastric fluid
without enzymes, citrate buffer medium pH
4.5 and phosphate buffer medium pH 6.8 or
simulated intestinal fluid without enzyme.
The dissolution test was conducted to
compare the dissolution profile between the
test product and the innovator product. This
test is also a preliminary study before the in
vivo bioequivalence test is performa (FDA,
2016).
In general, the method for in vitro
dissolution test is divided into three main
groups including: the method of variance
analysis (ANOVA) (FDA, 2015), the
dependent method (USP, 2011) and the
independent method (FDA, 2016; USP,
2011). The ANOVA-based method does not
depend on curve fitting procedures and
dissolution data is used in native form or as
simple transformation and its analysis is able
to show the difference between profile and
dissolution levels. Characterization of
model-dependent or model-independent
method depends on the value that used to
perform the calculation. The model-
dependent method however, is based on
different mathematical functions, which
describes the dissolution profile. Once the
corresponding function has been selected and
the dissolution profile is evaluated depending
on the derivative model parameter (UPS,
2011).
Atorvastatin is one of the most
common synthetic statins in the world. This
drug patent runs out in 2011 (Brunton et al.,
2008). This drug is at the top of the list of
drugs with the largest sales for many years
until 2011 (Bartholow, 2016). The price of
this drug was quite expensive. Therefore,
once the patent of atorvastatin is exhausted,
many emerging products copy (generic
named trade and generic). Drug copy is
defined as a drug containing an active
substance with the same composition,
strength, dosage form, route of
administration, indication and posology with
approved Drug (BPOM RI, 2011). The
existence of generic trademarked and generic
copies of atorvastatin may be an alternative
choice for hyperlipidemic patients for
reducing the burden of expensive drug costs.
Based on the solubility and
permeabilitas aspects, atorvastatin is
included non-soluble but highly permeable
compounds (Biopharmaceutics Classification
System case 2, BCS II) (Zakinleve et al.,
2012) Dissolution is generally a rate limiting
step in BCS II compounds. Dissolution test is
one of the most important quality control for
pharmaceutical dosage that can be used to
predict bioavailability. The dissolution
profile of a drug is directly related to its
pharmacological activity because it is a
prerequisite for drug absorption and clinical
response. The in vitro dissolution rate and
bioavailability relationships were formulated
in the form of IVIVC (in vitro-in vivo
correlation) (Popy et al., 2012; Cardot, 2007).
The purpose of this review is to find
out whether different dissolution profile
methods can be applied in conducting
comparative dissolution test studies of
atorvastatin and evaluating each method of
different calculation methods to obtain
dissolution profile values.
METHOD
The data collection was done by
literature study by collecting data from
various research which was published in
accredited journals. Data are also collected
from trusted institutions, such as the World
Health Organization and the Ministry of
Health of the Republic of Indonesia.
Secondary data are also obtained from books
on biopharmaceutics.
The obtained data are qualitative
and quantitative data. Qualitative and
quantitative data are processed through
several steps of selecting and simplifying the
data then presented in the form of narrative
sentences. Then the conclusion gradually was
taken based on the development of data
acquisition.
RESULT AND DISCUSSION
Independent Modeling Method
This independent model method
will result in a dissolution profile value that
will provide a direct comparison of the
dissolution data. This independent model
method is divided into two type of tests, the
ratio test and f-factors (USP, 2011).
Ratio test was performed as a
percent ratio of diluted drugs, areas below the
dissolution curve, and the mean dissolution
time of the reference formulation with the test
formulation at the same sampling time. The
most common test ratio is done by comparing
of two mean dissolution times or mean
dissolution Time (MDTs), which can be
calculated using;
F-factors are divided into the
difference factor (f1) and the similarity factor
(f2). The difference factor calculates the
percentage difference between the two curves
at each point and measures the percentage of
errors across all time points using the
formula;
which Ri and Ti are the percentage of the
dissolved drug rather than the reference and
the test product at each sample poin (De
Oliviera et al, 2012).
Similarity factor, f2 can be calculated using
the formula;
Which Ri is the amount of solute
from the innovator tablet at a given time, and
Ti is the amount of solute from the test tablet
at any given time. In this formula, n is the
number of filtrate withdrawal time points, Rt
is the dissolution value of the comparator or
the innovator at time t and Tt is the
dissolution value for the test product at time
t. The dissolution profiles of both samples
can be expressed similarly if the value of f1
lies between 0 and 15 and f2 is between 50
and 100. (De Oliviera et al, 2012).
Dependent Modeling Method
The dependent modeling method is
a mathematical method that used extensively
to present the parametric of dissolution data.
Quantitative interpretation of the value
obtained in dissolution testing is easier by
using mathematical equations, which express
an API release profile that works for some
parameters associated with a pharmaceutical
dosage form. Some of the most relevant and
frequently used mathematical models as well
as those describing the multipoint dissolution
profiles (De Oliviera et al, 2012).
Method of ANOVA Model
In this model, the percentage
dissolved drug is the dependent variable and
time is a recurring factor. Sources of variation
are time, drug products, and interactions
between time and drug products. The
experiment started with a multivariate
approach (MANOVA). MANOVA was able
to test whether there was a significant
difference between medicinal products with a
percentage that dissolved over Time (De
Oliviera et al, 2012).
Comparative Dissolution Test of
Atorvastatin
The dissolution of atorvastatin tablet
was performed using a Type II dissolution
device with a speed of 75 rpm, a 0.05 M
phosphate buffer medium, pH 6.8, 900 ml
volume. The dissolution filtrate filtration was
carried out at 5th, 10th, 15th, 30th, and 60th
minutes. The filtrate was taken from the area
Table 1. Physical test results of atorvastatin tablet samples criterion (Aini et al., 2015).
Sample Hardness
(Newton)
Innovator 85,7
Brand 70,8
Generic 76,5
between the surface and the oar, not less than
1 cm from the tube wall. After the filtrate is
taken, the dissolution medium is immediately
added to the amount of filtrate volume taken.
The sample filtrate was tested using HPLC.
The level data obtained from each dissolution
sampling point is drawn into a graph to see
the dissolution profile. Assessment of the
brand, and generic drug sample profiles are
done by comparing with the dissolution
profile of the innovator. This assessment is
done by calculating the factors of difference
and similarity factors (Hasson, 2010).
20 tablets of each sample were
pollinated and weighed which equivalent to 5
mg of atorvastatin then dissolved in 10.0 ml
methanol p.a. This solution is then taken as
much as 0.5 ml and diluted using methanol
p.a to 10.0 ml. The diluted solution was then
analyzed using HPLC. Atorvastatin analysis
with HPLC was carried out using C18
column with acetonitrile-buffered sodium
acetate buffer phase (55:45) which flowed
with isocratic conditions at a flow rate of 1.2
mL/min. The chromatogram was detected
using a PDA detector at a wavelength of 241
nm (Hasson, 2010).
Three samples of atorvastatin tablets
consisting of one innovator sample, one
brand sample, and one generic sample were
investigated for their dissolution profile,
grade, and physical quality.
Fragility Average Disolved
(%) Weight Time
(mg) (minutes)
0,08 307,3 0,9
0,27 257,7 0,7
0,06 403,4 35,6
 A good tablet should be tough
enough to hold, not easy to break, and not
fragile during packaging, distribution, and
storage until drug is used. For that, the
hardness test and tablet fragility. Based on the
literature, tablet hardness is considered to be
at least 4 kg or about 39.33 Newton (Kramer,
2009).
The three test samples have average
hardnesses ranging between 70 and 85
Newton so it can be said that all three have
good hardness. For fragility tests, the sample
of film-coated tablets is eligible if the lost
weights are not more than 1.0% of the initial
weight and no tablets are destroyed.15 The
three samples also meet this criterion (Aini et
al., 2015).
The dissolution test of atorvastatin
tablet was done using FDA method because
there is no dissolution test method for this
tablet in reference book like Farmakope
Indonesia, USP, and British Pharmacopoeia.
Tests were performed on each sample with
filtrate filtrate taking at 5th, 10th, 15th, 30th,
45th, and 60th minutes. Meanwhile, the
levels of the active substances contained in
the three samples met the general
requirements for the content of the active
substance in the tablet, 90-110 % Orange
criterion (Aini et al., 2015).
The results of the dissolution of the
three samples are plotted in graphical form
and can be seen in Figure 1.
Innovator
Brand
Generic
From the graph in Figure 1 it can be
clearly seen that the generic sample
dissolution profile is not similar to brand and
generic sample. In a generic sample, the
active substance is slowly dessolute without
a sharp spike in the first 5 minutes as in a
generic and generic named innovator sample.
Generally, the active substance in film-coated
tablet has been dissolved more than 70% in
the 15th minute. However, the generic
sample in this study only reached 70%
dissolution rate in the 30th minute. At the end
of the test time (60 minutes), it can be seen
that the levels of the active substance released
from the generic sample turn out to be larger
than the generic and brand samples criterion
(Aini et al., 2015).
To declare the similarity of the
dissolution profile between the copy tablet
and its innovator, the calculation of the
difference factor (f1) and the profile
similarity factor (f2). The apparent
differences in dissolution patterns in the
generic samples are confirmed using the
calculations of f1 and f2, and the result is that
the values f1 and f2 generic samples to the
innovators are 34.81 and 21.2, respectively.
The value is outside the equality requirement
so it can be stated that the generic sample
dissolution profile is different from the
innovator sample. The relationship between
time disintegration and dissolution can be
seen from these results. Generic samples
based on testing have an average
disintegration time over 30 minutes also take
a long time to be decolorized (Kramer, 2009).
This sample is only 85% dissolved in about
45 minutes criterion (Aini et al., 2015).
There are many factors that can be
the cause of dissolution profile difference
between innovator and generic drugs, such as
formulation, tablet forming, amount and type
of excipients Led (Allen et al., 2011).
Therefore, the final properties of a
preparation, such as bioavailability and
stability, depending on the selected excipient,
the amount of excipients employed, and their
interaction with the active substance or the
fellow excipient. The slower dissolution of
generic tablets can also be attributed to the
greater weight of excipients compared to
those used in generic tablets of innovative
tablets and tablets so that the nature and
quality of the excipients will greatly affect the
time of disintegration and dissolution that
ultimately affects the release of the active
ingredient (Augsurger et al., 2008).
The preferred instant-release oral
tablet dosage is usually a hard tablet but
quickly dessoluted. The tablet has resistance
during the production process, packaging,
and distribution, but quickly destroyed so that
the active substance can be released
immediately and does not delay the time it
takes the drug to cause the effect. Excipients
that affect the release of active substances
include binders, glidant, and lubricants. The
binding agent is required because the tablet is
expected to meet the friability requirement
which aims to not be damaged at the time the
drug is distributed. Meanwhile, the
destructive agent aims to quickly break down
the drug, usually through the mechanism of
absorbing fluid that makes the drug bubble
and then destroyed. In addition to binders and
crushers, other excipients that can affect
dissolution are lubricants. Too many
lubricants, which are usually hydrophobic,
will inhibit the destruction of the tablet and
the release of the active substance.
Research on the dissolution of
dosage of atorvastatin tablets has previously
been conducted in several countries,
including Bangladesh, Iraq, Brazil, and
Nigeria. In the research articles in these
countries, results are also obtained that
indicate that the dissolution profiles of some
tablets generic and generic trademarks are not
similar to dissolution profiles of innovator
tablet (Yunarto, 2010).
CONCLUSION
Based on the analysis of these
methods, it can be concluded that each
method has different characteristics in
looking for dissolution profiles. The labeled
atorvastatin inovator and generic samples of
tablets meet all the physical requirements of
the tablet, while generic atorvastatin tablets
do not meet any of the tablet's physical
requirement. The sample dissolution profile
of a generic named atorvastatin tablet is
similar to that of the innovator, while the
generic atorvastatin dissolution profile is not
similar to the dissolution profile of the
innovator. The three tested samples met the
requirements of active substance levels in
tablets.
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